4-benzylidene-5-oxo-2-phenyl-1-cyclopenteneacetic acid and analog thereof

ABSTRACT

Preparation of 4-benzylidene-5-oxo-2-phenyl-1-cyclopenteneacetic acid and congeners, and valuable biological properties thereof including antibacterial activity, are disclosed.

United States Patent [191 Chinn Q June 28, 1974 4-BENZYLIDENE-S-OXO-Z-PHENYL-l- CYCLOPENTENEACETIC ACID AND ANALOG THEREOF Leland J. Chinn, Morton Grove, Ill.

Assignee: G. D. Searle & Co., Chicago, Ill. Filed: Apr. 6, 1973 Appl. N0.: 348,528

Inventor:

References Cited UNITED STATES PATENTS 6/1973 Kathawala 260/515 R OTHER PUBLICATIONS Beilstein Handbuch der Organischer Chemie 10 pp. 784-785, (1927) Ermili et al. C.A. 6705d (1963).

Primary Examiner-Lorraine A. Weinberger Assistant Examiner-John F. Terapane Attorney, Agent, or Firm-John M. Brown Preparation of 4-benzylidene-5-oxo-2-phenyl-1- cyclopenteneacetic acid and congeners, and valuable biological properties thereof including antibacterial activity, are disclosed.

ABSTRACT 21 Claims, N0 Drawings CYCLOPENTENEACETIC ACID AND ANALOG THEREOF R ficmcoon. Cloo wherein n represents a positive integer less than 8. It follows that by di(lower alkyl)amino(lower alkyl) is meant dimethylaminomethyl, dimethylaminoethyl, diethyl=aminoethyl, diethylaminopropyl, di-

propylaminobutyl, etc., the lower alkyl constituents 35 contemplated in each occurrence being defined as before. Among these di(lower alkyl)amino=(lower alkyl) groupings, those of the formula wherein n and n' represent positive integers less than 4 and 3, respectively, are preferred.

The halogens contemplated in the introductory formula are fluorine, chlorine, bromine, and iodine, among which fluorine and chlorine are preferred.

Lower alkoxy. designates a radical of the formula O lower alkyl.

in which lower alkyl has the meaning previously assigned.

The positioning of the moieties represented by R and R" in the phenyl nuclei to which they attach is not critical, ortho, meta, and para locations alike being contemplated.

Equivalent to the foregoing compounds for the purposes of this invention are the alkali metal, alkalineearth metal, ammonium, and lower alkylated ammonium salts of the acids contemplated by the introductory formula when R therein represents hydrogen. By lower alkylated ammonium is meant a cation of the formula NHXlower alkyl) wherein lower alkyl is defined as above and x represents a positive integer less than 4. Likewise equivalent are complexes of the aforesaid acids and their salts, as

also the acid addition salts of the basic esters of this invsnti n heriaathsfqrm la wherein R and R" are defined as before, R represents di(lower alkyl)amino(lower alkyl), and T represents one equivalent of an anion for example, chloride, bromide, iodide, nitrate, phosphate, sulfate, sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate, toluenesulfonate, acetate, lactate, succinate, malate,

maleate, tartrate, citrate, gluconate, ascorbate, benzoate, cinnamate, or the like which, in combination with the cationic portion of the enforrnulated salt, is neither biologically nor otherwise undesirable.

Those skilled in the art will recognize that the comring is saturated can and do exist in more than one stereochemical configuration: The acetic acid side-chain and the adjoining phenyl substituent can each be situ- .'ate either above or below the plane of the ring and, by the same token, either cis or trans with respect to each other. Both cis and trans configurations, as also mixtures thereof, are contemplated herein, albeit the trans configurations are preferred.

The compounds to which this invention relates are useful by reason of their valuable biological properties. Among these properties is antibiotic activity, and a particular manifestation of ssuch activity is the capacity of the instant compounds to inhibit the growth of Erwinia 40 sp. A standardized test for this antibacterial effect is described in US; Pat. No. 3,682,951. The product of Ex amples 5, 9, 15C, and 17 hereinafter were active at concentrations of 1,000 mcgm./ml. in this test.

Certain of the compounds of this invention are 5 antiinflammatory for example, the products of Examples l2, 13, 15C, 23, and 26. Further, certain of the compounds are antihypertensive for example, the products of Examples 26 and 27- and/or bradykinin 23 and 25.

pounds of this invention wherein the five-membered- Preparation of the instant compounds proceeds by prolonged contact in a nitrogen atmosphere between a substituted acetic acid of the formula CHO 3 and potassium hydroxide, using ethanol as a solvent, followed by acidification with hydrochloric acid. The resultant product, which has the formula CHQOOOH "afraid. aaairarireai or aikanriaaramagmas being warmed with the metal hydroxide in ethanol, the ammonium salt on prolonged contact with excess ammonia q.s. saturation in 2-propanol, a lower alkylated ammonium salt by contacting in ether with an amine of the formula i NH lower alkyl and a lower alkyl ester by heating with an alcohol of the formula lower alkylOH in the presence of sulfuric acid. (R, R", x, and the dotted line retain the meansings previously assigned.) From the potassium salt of the aforesaid product, upon heating with a di(lower alkyl)amino(lower alkyl) chloride in 2-propanol, the corresponding basic ester is obtained. A mixture of such ester with an inorganic or strong organic acid wherein the anionic portion is de-- fined by T above affords an acid addition salt.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their preparation. It will be apparent to those skilled in the art that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples 4O hereinafter set forth, temperatures are given in degrees,- centigrade and relative amounts of materials in parts by weight, except as otherwise noted.

EXAMPLE 1 4-Benzylidene-5-oxo-2-phenyl-l-cyclopenteneacetic r acid. A solution of 22 parts of 5-oxo-2-phenyl-lcyclo==penteneacetic acid [1. Proc. Roy. Soc. N. S. Wales, 70, 431 (1937)], 16 parts of benzaldehyde, and; l 1 parts of potassium hydroxide in 440 parts of 95 per-i cent ethanol is allowed to stand at room temperatures} in a nitrogen atmosphere for 18 hours. The resultantj mixture is partitioned between water and ether. The ether phase is discarded; the aqueous phase is acidifiedi with 20 percent hydrochloric acid. The resultant mix-1 ture is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and; stripped of solvent by vacuum distillation. The residue is 4-benzylidene-5-oxo-2-phenyll cyclopentene=acetic acid, having the formula 1 CHzCOOH 4 EXAMPLE 2 EXAMPLE 4 4-( m-Fluorobenzylidene )-2-( p-fluorophenyl )-5-oxol-cyclopenteneacetic acid. Substitution of 23 parts of 2-(p-fluorophenyl )-5-oxol -cyclopenteneacetic acid and 19 parts of m-fluorobenzaldehyde for the 5-oxo-2- phenyl-l-cyclopenteneacetic acid and benzaldehyde, respectively, called for in Example 1 affords, by the procedure detailed in the aforesaid example, 4-(mfluorobenzylidene)-2-( p-fluorophenyl )-5-ox0- l cyclopenteneacetic acid.

EXAMPLE 5 4-( p-Chlorobenzylidene )-2-( p-fluorophenyl )-5-oxol'cyclopenteneacetic acid. To a solution of 4 parts of Z-(p-fluorophenyU-S-oxol -cyclopenteneacetic acid in parts of percent ethanol containing 2 parts of potassium hydroxide was added 3 parts of pchlorobenzaldehyde. The resultant mixture is allowed to stand at room temperatures in a nitrogen atmosphere for 20 hours during which a crystalline precipitate forms. The precipitate is isolated by filtration, washed successively with ethanol and ether, and dried in air. It is thereupon taken up in a minimum amount of water, and the resultant solution is acidified with 20 percent hydrochloric acid. The voluminous precipitate which results is filtered off, washed with water, dried in air, and crystallized from ethyl acetate to give 4-(pchlorobenzylidene )-2-( p-fluorophenyl )5-oxol cyclo=penteneacetic acid melting at 246250.

' asarirraa clopen=teneacetic acid.

EXAMPLE 7 4-(p-Chlorobenzylidenel-2-(m-clilorophenyl)-5- oxo- 1 -cyclopenteneacetic acid. Substitution of 25 parts of 2-( m-chlorophenyl )-5-oxol -cyclopenteneacetic EXAMPLE 8 4-(p-Chlorobenzylidene)-2-(p-chlorophenyl)-5-oxo l-cyclopenteneacetic acid. To a solution of 4 parts of 2-(p-chlorophenyl)-5-oxol-cyclopenteneacetic acid [prepared from p-chloroacetophenone according to the procedure for preparing 2-(p-fluorophenyl)-5-oxo- 1-cyclo=penteneacetic acid from pfluoroacetophenone described in US. Pat. No. 3,101,346] in approximately 80 parts of 95 percent ethanol containing 2 parts of potassium hydroxide is added 3 parts of p-chlorobenzaldehyde. The resultant mixture is allowed to stand at room temperatures in a nitrogen atmosphere for 19 hours during which a crystalline precipitate forms. The precipitate is filtered off, successively washed with ethanol andether, dried in air, and suspended in volumes of water. A slight excess of concentrated hydrochloric acid is introduced, and the resultant mixture is allowed to stand at room temperatures for 3 hours. Insoluble solids are filtered out, washed with water, dried in air, and recrystallized from ethyl acetate to give 4-(p-chlorobenzylidene)-2- p-chlorophenyl )-5-oxo- 1 -cyclopenteneacetic acid melting at 268270. v

EXAMPLE 9 2-(p-Fluorophenyl)-4-(p-methoxybenzylidene)-5- oxo-1-cyclopenteneacetic acid. To a solution of 10 parts of potassium hydroxide in 400 parts of 95 percent ethanol are consecutively added 20 parts of 2-(pfluorophenyl)-5-oxo-l-cyclopenteneacetic acid and approximately parts of p-methoxybenzaldehyde. The resultant mixture is allowed to stand at room temperatures in a nitrogen atmosphere for hours during whicha crystalline precipitate forms. The precipitate is isolated by filtration, washed successively with ethanol and ether, dried in air, and taken up in a minimum amount of water. To the aqueous solution is added sufficient 20 percent hydrochloric acid to induce acidity. The resultant precipitate is filtered off, washed with water, dried in air, and crystallized from ethyl acetate to give 2-(p-fluorophenyl)-4-(p-methoxybenzylidene)- 5-oxo- 1 -cyclopenteneacetic acid melting at 234.5236.5.

EXAMPLE l0 Methyl 2-(p-fluorophenyl)-4-(pmethoxybenzylidene )-5-oxo- 1 -cyclopenteneacetate. A mixture of 4 parts of 2-(p-fluorophenyl)-4-(pmethoxybenzylidene )-5-oxo- 1 -cyclopenteneacetic acid, 7 parts of concentrated sulfuric acid, and approximately 300 parts of methanol is heated at the boiling point under reflux for 3 hours, then concentrated to one-half volume by vacuum distillation in a nitrogen atmosphere. To the concentrate is added 5 volumes of water followed by aqueous 5 percent sodium bicarbonate q.s. neutrality. The gummy precipitate which forms crystallizes on standing. Isolated by filtration, washed with water, dried in air, and crystallized from ether, it affords methyl 2-(p-fluorophenyl-4-(pmethoxybenzylidene)-5-oxol -cyclopenteneacetate melting at approximately l60'l61.

EXAMPLE 1 1 2-(o-Chlorophenyl)-4-(o-ethoxybenzylidene)-5-oxol-cyclopenteneacetic acid. Substitution of 25 parts of 2-(o-chlorophenyU-S-oxo- 1 -cyclopenteneacetic acid and 23 parts of o-ethoxybenzaldehyde for the 5-oxo-2- phenyl-l-cyclopenteneacetic acid and benzaldehyde, respectively, called for in Example 1 affords, by the procedure detailed in the aforesaid example, 2-(0- chlorophenyl)-4-(o-ethoxybenzylidene)-5-oxo-1- cyclopenteneacetic acid.

EXAMPLE 12 2-(p-Chlorophenyl)-4-(p-rnethoxybenzylidene)-5- oxo-l-cyclopenteneacetic acid. To a solution of 100 it forms is filtered off, washed with. water, dried in air, 0

and crystallized from ethyl acetate to give 2-(pchlorophenyl )-4-(p-methoxybenzylidene )-5-oxo- 1 cyclopenteneacetic acid melting at 228.5232.'5.

EXAMPLE 13 Methyl 2-( p-Chlorophenyl )-4-( pmethoxybenzylidene )-5-oxol -cyclopenteneacetate. A mixture of 3 parts of 2-(p-chlorophenyl)-4-(pmethoxybenzylidene )-5-oxol -cyclopentene=acetic acid, approximately 2 parts of concentrated sulfuric acid, and parts of methanol is heated at the boiling point under reflux for 3 hours, then concentrated to approximately one-half volume by vacuum distillation. The residue is diluted with 5 volumes of water, and the resultant solution is neutralized with aqueous 5 percent sodium bicarbonate. The solid which precipitates is filtered out, washed with water, dried in air, and crystallized from ether to give methyl 2-(p-chlorophenyl)-4- (p-methoxybenzylidene )-5-oxol -cyclopenteneacetate melting at approximately 153154.

EXAMPLE 14 carbonate. The mixture is then extracted with ether.

The ether extract is washed with water, dried over anhydrous sodium sulfate, and thereupon stripped of sol vent by vacuum distillation. The product thus obtained is ethyl 2-(p-chlorophenyl)-4-(pmethoxybenzylidene)-5-oxo- 1 -cyc1open=teneacetate.

EXAMPLE 15 A. Potassium Z-(p-chlorophenyl)-4-(p-methoxy= benzylidene)--oxo-l-cyclopenteneacetate. To a solution of 66 parts of 2-( p-chlorophenyl )-4-( pmethoxybenzylidene)-5-oxol -cyclopenteneacetic acid in a minimum amount of ethanol is added a solution of parts of potassium hydroxide in parts of water. The precipitate which forms is filtered out, washed with ether, and dried in air. The product thus isolated is potassium 2-(p-chlorophenyl)-4-(pmethoxybenzylidene )-5-oxolcyclo=penteneacetate.

B. 2-Diethylaminoethyl 2-(p-chlorophenyl)-4-(pmethoxybenzylidene )-5-oxol -cyclopenteneacetate. A mixture of 6 parts of potassium 2-(p-chlorophenyl)-4- (p-methoxybenzylidene )-5 -oxol -cyclopenteneacetate, 3 parts of diethylaminoethyl chloride, and 130 parts of 2-propanol is stirred and heated at the boiling point under reflux for 24 hours, whereupon most of the solvent is removed by vacuum distillation. The residue is triturated with water. The resultant mixture is extracted with ether. The ether extract is dried over why drous sodium sulfate and then stripped of solvent by vacuum distillation. The residue is Z-diethylaminoethyl 2-( p-chlorophenyl )-4-( p-methoxybenzylidene )-5-oxol-cyclopenteneacetate.

C. 2-Diethylaminoethyl 2-(p-chlorophenyl)-4-(pmethoxybenzylidene )-5-oxol -cyc1openteneacetate oxalate. To a solution of 10 parts of 2- diethylaminoethyl 2-(p-chlorophenyl)-4-(pmethoxybenzylidene )-5-oxol -cyclopentene=*acetate in 8 parts of 95 percent ethanol is added a solution of 2 parts of oxalic acid in 5 parts of ethanol. The solid which forms is filtered off, washed with ether, and dried in air, to give 2-diethylaminoethyl 2-(p-chlor0phenyl)- 4-( p-methoxybenzylidene)-5-oxol cyclopenteneacetate oxalate melting at l46.5-149.5.

D. 2-Diethylaminoethyl 2-(p-chlorophenyl)-4-(pmethoxybenzylidene )-5-oxo- 1 cyclopenteneacetate hydrochloride. To a solution of 100 parts of 2- diethyl=aminoethyl-2-(p-chlorophenyl)-4-(pmethoxybenzylidene )-5-oxol -cyclopenteneacetate in 160 parts of 2-propanol is added a solution of 13 parts of hydrogen chloride in 40 parts of 2-propanol. The resultant mixture is chilled and then diluted with sufficient ether to effect precipitation of a gum. The supernatant liquid is decanted and the gum repeatedly triturated with ether to afford 2-diethylaminoethyl 2-(pchlorophenyl)-4-(p-methoxybenzylidene)-5-oxolcyclopenteneacetate hydrochloride as a powder melting in the range 88l05.

EXAMPLE l6 '3-Dimethylaminopropyl 2-(p-chlorophenyl)-4-(pmethoxybenzylidene )-5-oxo l -cyclopenteneacetate. Substitution of 3 parts of dimethylaminopropyl chloride for the diethylaminoethyl chloride called for in Example 15B affords, by the procedure there detailed, 3- dimethylaminopropyl 2-(p-chlorophenyl)-4-(pmethoxybenzylidene)-5oxo-1-cyclo=penteneacetate.

EXAMPLE l7 4-(p-Chlorobenzylidene )-2-(p-methoxyphenyl)-5- oxo-l-cyclopenteneacetic acid. To a solution of 2 parts of potassium hydroxide in 80 parts of 95 percent ethanol are consecutively added 4 parts of 2-(pmethoxypheny1)-5-oxol cyclo=penteneacetic acid [Zhur. Obschchei. Khim., 28, 528 (1968)] and 3 parts of p-chlorobenzaldehyde. The resultant mixture is allowed to stand at room temperatures in a nitrogen atmosphere for 23 hours. The solid precipitate which forms is filtered off, successively washed with ethanol and ether, dried in air, and taken up in a minimum amount of water. To the aqueous solution is added a slight excess of approximately 20 percent hydrochloric acid. The resultant precipitate is filtered off, washed with water, dried in air, and crystallized from ethyl acetate to give 4-(p-chlorobenzylidene)-2-(pmethoxyphenyl)-5-oxol -cyclopenteneacetic acid melting at 227229.

EXAMPLE 18 Z-(m-Ethoxyphenyl)-4-(o-fluorobenzylidene)-5-oxol-cyclopenteneacetic acid. Substitution of 26 parts of Z-(m-ethoxyphenyl )-5-oxol -cyclopenteneacetic acid (US. Pat. No. 3,019,233) and 19 parts. of ofluorobenzaldehyde for the 5-oxo-2-phenyl-lcyclopenteneacetic acid and benzaldehyde, respectively, called for in Example 1, affords, by the procedure detailed in the aforesaid example, 2-(methoxyphenyl )-4-(o-fluoroben2ylidene )-5-oxol cyclopetene=acetic acid.

EXAMPLE 19 4-( p-Methoxybenzylidene )-2-( p-methoxyphenyl )-5 oxo-l-cyclopenteneacetic acid. To a solution of 34 parts of potassium hydroxide in 1,360 parts of percent ethanol are consecutively added 67 parts of 2-( p-methoxyphenyl )-5-oxol-cyclopenteneacetic acid and 550 parts of p-methoxy=benzaldehyde. The resultant solution is allowed to stand at room temperatures in a nitrogen atmosphere for 20 hours, whereupon the precipitate which forms is filtered off, washed with ethanol, dried in air, and then taken up in a minimum amount of water. To the aqueous solution is added sufficient concentrated hydrochloric acid to induce acidity. The precipitate which forms is filtered out, washed with water, dried in air, and crystallized from ethyl acetate to give 4-(p-methoxybenzylidene)- 2-(p-methoxyphenyl)-5-oxol -cyclopenteneacetic acid which melts at 2085-21 1.5 and resolidifies to melt again at 227230.

EXAMPLE 20 Methyl 4-(p-methoxybenzylidene)-2-( pmethoxyphenyl )-5-oxol cyclopenteneacetate. A mixture of l 1 parts of 4-(p-methoxybenzylidene)-2-(pmethoxyphenyl )-5-oxol -cyclo=penteneacetic acid, 7 parts of concentrated sulfuric acid, and 320 parts of methanol is heated at the boiling point under reflux for 3 hours, then concentrated to one-half volume by vacuum distillation in a nitrogen atmosphere. The concentrate is diluted with 5 volumes of water, and the resultant mixture is neutralized with aqueous 5 percent sodium bicarbonate. The gum which forms is isolated by decanting the liquid phase therefrom, washed with water, dried in air, and crystallized from ether to give methyl 4-(p-methoxybenzylidene)-2-(pmethoxyphenyl )-5-oxol -cyclopenteneacetate melting at 143.5-l45.5.

EXAMPLE 21 4-(o-Ethoxybenzylidene )-2-(m-ethoxphenyl)-5- oxol -cyclopenteneacetic acid. Substitution of 26 parts of 2-( m-ethoxyphenyl )--oxol cyclopenteneacetic acid and 23 parts of o-ethoxybenzaldehyde for the 5-oxo-2-phenyl-lcyclopenteneacetic acid and benzaldehyde called for in Example 1, respectively, affords, by the procedure detailed in the aforesaid example, 4-(o-ethoxybenzylidene )-2-(methoxphenyl)-5-oxo-1- cyclopenteneacetic acid.

EXAMPLE 22 HzCOOH y EXAMPLE 23 S-(p-Fluorophenyl)-3-(p-methoxybenzylidene)-2- oxocy'clopentaneacetic acid triethylamine salt. A solution of 40 parts'of 5-(p-fluorophenyl)-2oxocyclopentaneacetic acid (U.S. Pat. No. 3,101,346) and parts of potassium hydroxide in a mixture of 33 parts of pmethoxybenzaldehyde and 800 parts of 95 percent ethanol is allowed to stand at room temperatures in a nitrogen atmosphere for 18 hours. The reaction mixture is then partitioned between water and ether. The ether is discarded. The aqueous phase is acidified with 22 percent hydrochloric acid. The resultant mixture is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by distillation. The residue is taken up in 140 parts of ether. To the ether solutionis added 11 parts of triethyl=amine. The gum which forms initially solidifies on standing. The solid is filtered off and crystallized from a mixture of 2-propanol and ethol to give a triethylamine salt of 5-(p-fluorophenyl)-3-(pmethoxybenzylidene)-2-oxocyclo=pentaneacetic acid melting at 1 l2.5-l 14.5 and which can be represented by the formula EXAMPLE 24 5-(o-Chlorophenyl)-3-(o-ethoxybenzylidene)-2- oxocyclopentaneacetic acid. Substitution of 25 parts of 5-(o-chlorophenyl)-2-oxocyclopentaneacetic acid 10 [prepared by hydrogenating 2-(o-chlorophenyl)-5-oxol-cyclopentene=acetic acid using palladium-oncharcoal catalyst, in accordance with the procedure for preparing 5(p-fluoro=phenyl)-2-oxocyclopentaneacetic acid from 2-(p-fluorophenyl)- 5-oxo-1- cyclopenteneacetic acid described in U.S. Pat. No. 3,101,346] and 23 parts of o-ethoxybenzaldehyde for the 5-oxo-2- phenyl-l-cyclopenteneacetic acid and benzaldehyde, respectively, called for in Example 1, affords, by the procedure detailed. in the aforesaid example, 5-(o-chlorophenyl)- 3-(o-ethoxybenzylidene)- 2-oxocyclopentaneacetic acid.

EXAMPLE 25 3-(p-Methoxybenzylidene)-5-(p-methoxyphenyl)-2- oxocyclopentaneacetic acid. A solution of 40 parts of potassium hydroxide in 1,600 parts of ethanol is sufficiently warmed to permit dissolving therein parts of 5 (p-methoxyphenyl)-2- oxocyclopentaneacetic acid [Zhur. Obschchei. Khim., 28, 528 (1968]. To this solution is added 66 parts of p-methoxybenzaldehyde. The resultant mixture is allowed to stand at room temperatures in a nitrogen atmosphere for 24 hours, where upon it is partitioned between water and ether. The ether phase is discarded. The aqueous phase is acidified with 22 percent hydrochloric acid. The mixture which results is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, stripped of solvent by distillation, and crystallied from a mixture of ether and hexane to give 3-(pmethoxybenzylidene)-5-(p-methoxypheny)-2- oxocycl0=pentaneacetic acid melting at 97-101.

EXAMPLE 26 Methyl 3-(p-Methoxybenzylidene)-5-(pmethoxyphenyl)- 2-oxocyclopentaneacetate. A solution of 30 parts of 3- (p-methoxybenzylidene)-5- (pmethoxyphenyl)-2-oxocyclopentane=acetic acid and 22 parts of concentrated sulfuric acid in 960 parts of methanol is heated at the boiling point under reflux for 2 hours, then concentrated to somewhat less than onehalf volume by vacuum distillation. The concentrate contains a crystalline precipitate. Approximately 5 volumes of water is introduced, followed by sufficient aqueous 5 percent sodium bicarbonate to effect neutrality. Insoluble solids are thereupon filtered out, washed with water, dried in air, and crystallized from a mixture of ethyl acetate and ether to give methyl 3- (p-methoxybenzyli=dene)-5-(p-methoxyphenyl)-2- oxocyclopentaneacetate melting at approximately l43.5-144.5.

EXAMPLE 27 methoxyphenyl)-2-oxocyclopentaneacetate melting at approximately 9l-92.

EXAMPLE 28 wherein R represents hydrogen, lower alkyl, or di(- lower alkyl)amino(lower alkyl); R and R" each repre-;

sent hydrogen, halogen of atomic number less than 18 or lower alkoxy; and the dotted line represents thelocus of an optional double bond.

2. A compound according to claim 1 having the formula R CHzCOOR wherein R represents hydrogen, lower alkyl, or di(- lower alkyl) amino (lower alkyl) and R and R" each represent hydrogen, halogen of atomic number less than 18, or lower alkoxy.

3. A compound according to claim 1 having the formula R CHiCOOR wherein R represents hydrogen or lower alkyl and R and R" each represent hydrogen, halogen of atomic number less than 18, or lower alkoxy.

4. A compound according to claim 1 having the formula halogen wherein each halogen has an atomic number less than 18.

5. A compound according to claim 1 which is 4-(pchlorobenzylidene)-2-(p-fluorophenyl )-5-oxol cyclopenteneacetic acid.

6. A compound according to claim 1 having the formula halogen halogen ficmcoon CH 0 wherein the halogen has an atomic number less than 18.

7. A compound according to claim 1 which is 2-(pchlorophenyl )-4-( p-methoxybenzylidene-5-oxol cyclopenteneacetic acid.

8. A compound according to claim 1 having the formul halolgen H; C O 0-1ower alkyl moo-Germ 0 wherein the halogen has an atomic number less than 18.

9. A compound according to claim 1 which is methyl 2-(p-chlorophenyl)-4-(p-methoxybenzylidene)-5-oxol-cyclopenteneacetate.

10. A compound according to claim 1 having the forn iula 44444 a wherein n and n represent positive integers less than 4 and 3, respectively.

11. A compound according to claim 1 which is 2- diethylaminoethyl 2-(p-chlorophenyl)-4-(pmetho xe zenzy dw -Q pwtsnee sfiat 12. A compound ac'cor'dngio anniiianfignazrsimula halogen lower alkox 5 lower alkoxy y cmcoon --CH= halogen CH: C 0 0H wherein the halogen has an atomic number less than CH 0 I0 1 17. A compound according to claim 1 which is S-(pfluorophenyl)-3-(p-methoxybenzylidene)-2-oxocyclo= pentaneacetic acid.

' I wherein the halogen has an atomic number less than l8.Ac0m und accordin t cl 'm 1 h th f 13. A compound according to claim 1 which is 4-(pl5 vmula p0 g 0 a] avmg e or cyclopenteneacetic acid. 14. A compound according to claim 1 having the for-5 lower alkoxy mula lower alkoxy I i lower alkoxy CH: C 0 OH lower alkoxy CH: C 0 OH Z Q 19. A compound according to claim 1 which is 3-(pmethoxybenzylidene)-5-(p-methoxyphenyl)-2- oxocyclo= pentaneacetic acid. 15. A compound according to claim 1 having the forfi A Compound accordmg to m having the mula l R on, o o o R r EH10 O'0-lower alkyl CH o G 40 moo-@mrp 0 wherein R represents hydrogen or lower alkyl and R and R" each represent halogen of atomic njmber less 21. A compound according to claim 1 which is meththan 18 or lower alkoxy. yl 3-(p-methoxybenzylidene)-5-(p-methoxyphenyl)-2- 16. A compound according to claim 1 having the for oxocyclopentaneacetate mula 

2. A compound according to claim 1 having the formula
 3. A compound according to claim 1 having the formula
 4. A compound according to claim 1 having the formula
 5. A compound according to claim 1 which is 4-(p-chlorobenzylidene)-2-(p-fluorophenyl)-5-oxo-1-cyclopenteneacetic acid.
 6. A compound according to claim 1 having the formula
 7. A compound according to claim 1 which is 2-(p-chlorophenyl)-4-(p-methoxybenzylidene-5-oxo-1-cyclopenteneacetic acid.
 8. A compound according to claim 1 having the formula
 9. A compound according to claim 1 which is methyl 2-(p-chlorophenyl)-4-(p-methoxybenzylidene)-5-oxo-1-cyclopenteneacetate.
 10. A compound according to claim 1 having the formula
 11. A compound according to claim 1 which is 2-diethylaminoethyl 2-(p-chlorophenyl)-4-(p-methoxy benzylidene)-5-oxo-1-cyclopenteneacetate.
 12. A compound according to claim 1 having the formula
 13. A compound according to claim 1 which is 4-(p-chlorobenzylidene)-2-(p-methoxyphenyl)-5-oxo-1-cyclopenteneacetic acid.
 14. A compound according to claim 1 having the formula
 15. A compound according to claim 1 having the formula
 16. A compound according to claim 1 having the formula
 17. A compound according to claim 1 which is 5-(p-fluorophenyl)-3-(p-methoxybenzylidene)-2-oxocyclo pentaneacetic acid.
 18. A compound according to claim 1 having the formula
 19. A compound according to claim 1 which is 3-(p-methoxybenzylidene)-5-(p-methoxyphenyl)-2-oxocyclo pentaneacetic acid.
 20. A compound according to claim 1 having the formula
 21. A compound according to claim 1 which is methyl 3-(p-methoxybenzylidene)-5-(p-methoxyphenyl)-2-oxocyclopentaneacetate. 